The Baltimore Longitudinal Study of Aging (BLSA), the Intramural NIA's current major research program on human aging, has been conducted at the Gerontology Research Center since 1958, and is now active at the NIA-ASTRA (Translational Research on Aging) Unit located at Harbor Hospital (Baltimore). The study continues to represent a consortium of scientists who work to characterize normal and pathological aging. The team of researchers currently managing the study is implementing major changes in its design and assessment technology. The primary scientific goals remain those that were reported in the original BLSA legacy: 1) to identify age-associated differences among individuals which are not explained by diseases, and 2) to characterize factors that affect the transitions from normal to pathological aging. However, new measures are being implemented that are aimed at gaining a better understanding of the effect of age and diseases on the process that leads to mobility disability and poor quality of life in many older adults. The focus is on an integrative and multidisciplinary approach, and the compensatory mechanisms that, naturally implemented at multiple levels (cells, tissues, organs, whole body, society) allow many older persons to maintain a high level of mobility, in spite of multiple pathological process. The study population is a cohort of volunteers that are followed for life over multiple follow-up visits. Many of the active participants have been in the study for more than 20 years, and some for as long as 44 years. In the future, a screening program will be implemented to longeve individuals that have maintained an extraordinary high level of physical and congnitive functioning. In the past, the BLSA has been the gold-standard reference for all epidemiological studies on aging. Important findings in the area of cardiovascular research, factors affecting the risk of prostate cancer, age-associated decline of cognitive function, muscle strength and bone strength were published even in recent years. Moving the BLSA to the ASTRA unit was vital to implementing some of the new knowledge in a clinical perspective. This goal will be pursued by conducting, in parallel, the BLSA ancillary studies that, being limited to a small number of participants and adressing a single, pre-formulated hypothesis, are more likely to provide information that can be directly applied in clinical medicine. The structure of the new BLSA design is based on three levels of measures: 1. The reference level is the level of behavior that is mostly influenced by physical and cognitive function. Accordingly, the BLSA includes comprehensive measures of physical and cognitive function from different perspectives; 2. The intermediate level includes measures of anatomical integrity and functionality of the physiological systems that are important for mobility: central nervous system, peripheral nervous system, muscle, bone and joints, delivery of substances important for energy production, sensory systems that provide feedback from the environment; 3. The third level includes the physiological systems that are important to maintain a stable biological homeostasis and include measures for immune function, hormones, oxidative stress/antioxidants, autonomic nervous system, nutritional intake, and physical activity. The hypothesis of the study is that a dysfunction of the systems that maintain the biological homeostasis is the primary cause of the age associated decline of physical function and of the development of frailty.